Differential effect of hypoxia on early endothelial–mesenchymal transition response to transforming growth beta isoforms 1 and 2

Doerr, Meghan; Morrison, Jodi; Bergeron, Lindsay H.; Coomber, Brenda L.; Viloria-Petit, Alicia

doi:10.1016/j.mvr.2016.08.001

Cited by 26 publications

(21 citation statements)

References 57 publications

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“…The association of Let-7d-3p and miR-574-3p with PR was observed 6 months after the index NSTE-ACS event. Let-7d-3p belongs to the Let-7 superfamily and has been previously shown to be an important inducer of vascular smooth muscle cell proliferation via K-RAS [41][42][43] . MiR-574-3p has been shown to be a marker of inflammation and vascular damage in patients with Type 2 Diabetes, as well as a promoter of vascular smooth muscle growth and a potential novel biomarker of coronary artery disease progression [44][45][46] .…”

Section: Discussionmentioning

confidence: 99%

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements

Becker

Kwee

Neely

et al. 2020

Sci Rep

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changes in platelet physiology are associated with simultaneous changes in microRnA concentrations, suggesting a role for microRnA in platelet regulation. Here we investigated potential associations between microRnA and platelet reactivity (pR), a marker of platelet function, in two cohorts following a non-St elevation acute coronary syndrome (nSte-AcS) event. first, non-targeted microRnA concentrations and pR were compared in a case (n = 77) control (N = 76) cohort within the larger TRILOGY-ACS trial. MicroRNA significant in this analysis plus CVD-associated microRNAs from the literature were then quantified by targeted rt-PCR in the complete TRILOGY-ACS cohort (N = 878) and compared with matched PR samples. Finally, microRNA significant in the non-targeted & targeted analyses were verified in an independent post NSTE-ACS cohort (N = 96). From the non-targeted analysis, 14 microRNAs were associated with PR (Fold Change: 0.91-1.27, p-value: 0.004-0.05). From the targeted analysis, five microRNAs were associated with PR (Beta: −0.09-0.22, p-value: 0.004-0.05). Of the 19 significant microRNAs, three, miR-15b-5p, miR-93 and miR-126, were consistently associated with pR in the tRiLoGY-AcS and independent Singapore post-AcS cohorts, suggesting the measurement of circulating microRnA concentrations may report on dynamic changes in platelet biology following a cardiovascular ischemic event.Despite advancements in its management, cardiovascular disease including non-ST elevation acute coronary syndrome (NSTE-ACS) remains a major cause of patient morbidity and mortality 1-4 . Antiplatelet therapies including P2Y 12 antagonists are used to treat NSTE-ACS acutely and in the longer-term. While measurements of platelet reactivity (PR) have facilitated the rapid quantification of anti-platelet medication efficacy, questions still remain about the utility of PR to predict clinical outcomes 5-8 . Platelet genetics and PR sub-studies from large-scale clinical trials have informed our understanding of individual variability in P2Y 12 inhibitor response, but genomic regulation of individual patient's PR has not been fully clarified 9-14 .Small non-coding ribonucleic acids (RNA) including microRNAs have emerged as potential regulators of PR in patients with cardiovascular disease 15 . MicroRNAs (miRNAs) are 18-22 nucleotide non-coding RNAs that play an essential role in gene modulation and expression and are established regulators of cardiovascular

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Section: Discussionmentioning

confidence: 99%

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements

Becker

Kwee

Neely

et al. 2020

Sci Rep

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“…Although EndMT is implicated in many diseases, the stimuli that trigger the initiation of this cellular differentiation and the mechanisms through which the transformation occurs remain elusive. Several signaling pathways are reported in EndMT, the most important being TGFβ binding (Doerr, Morrison, Bergeron, Coomber, & Viloria-Petit, 2016;Montorfano et al, 2014;Nakajima et al, 2000;E. M. Zeisberg et al, 2008E.…”

Section: Discussionmentioning

confidence: 99%

Isoform‐specific effects of transforming growth factor β on endothelial‐to‐mesenchymal transition

Sabbineni

Verma

Somanath

2018

Journal Cellular Physiology

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Endothelial-to-mesenchymal transition (EndMT) was first reported in the embryogenesis. Recent studies show that EndMT also occurs in the disease progression of atherosclerosis, cardiac and pulmonary fibrosis, pulmonary hypertension, diabetic nephropathy, and cancer. Although transforming growth factor β (TGFβ) is crucial for EndMT, it is not clear which isoform elicits a predominant effect. The current study aims to directly compare the dose-dependent effects of TGFβ1, TGFβ2, and TGFβ3 on EndMT and characterize the underlying mechanisms. In our results, all three TGFβ isoforms induced EndMT in human microvascular endothelial cells after 72 hr, as evidenced by the increased expression of mesenchymal markers N-cadherin and α-smooth muscle actin as well as the decreased expression of endothelial nitric oxide synthase. Interestingly, the effect of TGFβ2 was the most pronounced. At 1 ng/ml, only TGFβ2 treatment resulted in significantly increased phosphorylation (activation) of Smad2/3 and p38-MAPK and increased expression of mesenchymal transcription factors Snail and FoxC2. Intriguingly, we observed that treatment with 1 ng/ml TGFβ1 and TGFβ3, but not TGFβ2, resulted in an increased expression of TGFβ2, thus indicating that EndMT with TGFβ1 and TGFβ3 treatments was due to the secondary effects through TGFβ2 secretion. Furthermore, silencing TGFβ2 using small interfering RNA blunted the expression of EndMT markers in TGFβ1- and TGFβ3-treated cells. Together, our results indicate that TGFβ2 is the most potent inducer of EndMT and that TGFβ1- and TGFβ3-induced EndMT necessitates a paracrine loop involving TGFβ2.

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“…For example, even though both TGF‐β 1 and TGF‐β 2 induced EndMT in bovine aortic ECs (BAECs) cultured under hypoxic conditions, only TGF‐β 1 ‐induced phosphorylated‐Smad2 nuclear accumulation was enhanced under hypoxia. Whether the nuclear accumulation of phosphorylated Smad2 correlates with an increase in the TGF‐β 1 ‐induced transcriptional response was not investigated (Doerr et al, ). Such crosstalk between hypoxia and TGF‐β signaling mechanisms can also be regulated by the expression of different miRNAs.…”

Section: Developmental Signaling Pathways Regulating Endmtmentioning

confidence: 99%

Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

Sánchez‐Duffhues

Vinuesa

Dijke

2017

Developmental Dynamics

128

113

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The process named endothelial-to-mesenchymal transition (EndMT) was observed for the first time during the development of the chicken embryo several decades ago. Of interest, accumulating evidence suggests that EndMT plays a critical role in the onset and progression of multiple postnatal cardiovascular diseases. EndMT is controlled by a set of developmental signaling pathways, very similar to the process of epithelial-to-mesenchymal transition, which determine the activity of several EndMT transcriptional effectors. Once activated, these EndMT effectors regulate the expression of endothelial-and mesenchymalspecific genes, in part by interacting with specific motifs in promoter regions, eventually leading to the down-regulation of endothelial-specific features and acquisition of a fibroblast-like phenotype. Important technical advances in lineage tracing methods combined with experimental mouse models demonstrated the pathophysiological importance of EndMT for human diseases. In this review, we discuss the major signal transduction pathways involved in the activation and regulation of the EndMT program. Furthermore, we will review the latest discoveries on EndMT, focusing on cardiovascular diseases, and in particular on its role in vascular calcification, pulmonary arterial hypertension, and organ fibrosis. Developmental Dynamics 247:492-508,

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Differential effect of hypoxia on early endothelial–mesenchymal transition response to transforming growth beta isoforms 1 and 2

Cited by 26 publications

References 57 publications

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements

Circulating MicroRNA Profiling in Non-ST Elevated Coronary Artery Syndrome Highlights Genomic Associations with Serial Platelet Reactivity Measurements

Isoform‐specific effects of transforming growth factor β on endothelial‐to‐mesenchymal transition

Endothelial‐to‐mesenchymal transition in cardiovascular diseases: Developmental signaling pathways gone awry

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